Mesoporous Materials: Structure and Fabrication
Inorganic porous substances are classified by pore size. Those having pore sizes smaller than 2 nm are classified as microporous substances, between 2 and 50 nm are classified as mesoporous substances and larger than 50 nm are classified as macroporous substances. Porous inorganic materials are generally fabricated using a “sol-gel” process. Other methods used to fabricate porous solids include electrochemical methods and acid etching. A sol is a liquid solution containing a soluble precursor of the inorganic material of interest dissolved in an appropriate solvent. The most widely used family of sol-gel precursors are the alkoxides, compounds containing metal atoms linked to organic ligands via oxygen bridges, such as tetraethoxysilane, Si(—OCH2CH3)4 (TEOS), a precursor of silicon dioxide (silica). Alkoxides are popular because they are easily hydrolyzed by water, either partially or fully, according to the reactions:Si(—OR)4+H2O→HO—Si(—OR)3+R—OH (partial hydrolysis)   (1a)Si(—OR)4+4H2O→Si(—OH)4+4R—OH (full hydrolysis)   (1b)
Two partially or fully hydrolyzed precursor molecules can undergo a condensation reaction, whereupon two silanol groups (Si—OH) are replaced by a covalent bond that involves formation of a siloxane (Si—O—Si) bridge, according to the reaction:(OR)3Si—OH+HO—Si(OR)3→(OR)3Si—O—Si(OR)3+H2O (condensation)   (2)
Condensation reactions between hydrolyzed precursor molecules can continue indefinitely, resulting in larger and larger structures (particles, branched chains, linear chains, etc) in the sol. The morphology, size and growth rate of these species depend on the kinetics of the hydrolysis and condensation reactions, which in turn are determined by parameters such as number of hydrolysable ligands per precursor monomer, solution concentration, amount of water or presence of a catalyst or a surfactant, temperature, pH, agitation, etc. Given enough time, condensation reactions will lead to aggregation of the growing particles or chains and, eventually, a gel will form. A gel can be visualized as a very large number of cross-linked precursor monomers forming a continuous, macroscopic-scale, solid phase, which encloses a continuous liquid phase consisting of the remaining solution. In the final steps of the sol-gel process, the enclosed solvent is removed (generally by drying) and the precursor molecules cross-link (aging) resulting in the desired inorganic solid.
Sol-gel synthesis offers several advantages over other synthetic routes for the formation of mesoporous oxides. These include mild processing conditions (low temperature, low pressure, mild pH), inexpensive raw materials, no need for vacuum processing or other expensive equipment, and a high level of control over the resulting morphology and microstructure, particularly as it pertains to porosity. Regarding shape of the finalized product, there is essentially no limitation, since the liquid sol can be cast in any conceivable form before allowed to gel, including monoliths, thin films, fibers and micro- or nano-scale particles. Porosity can be controlled via an extensive number of different methods discussed later. At the most basic level, these methods can be classified according to whether or not additional chemicals are employed as sacrificial porogens/templates.
In the simplest sol-gel process no special porogen is added to the sol and the porosity of the final solid is determined by the amount of precursor branching or aggregation (via nucleation and growth mechanisms) before gelling. Such a porous solid phase is termed a xerogel. Average pore size, volume and surface area will increase with the size of precursor species prior to deposition. In one example, silica thin films deposited via dip-coating from a sol of neutral acidity (pH 7) were shown to be aggregates of dense particles with ˜100 nm radius and 65% overall pore volume (C. J. Brinker et al, in Ultrastructure Processing of Advanced Ceramics, eds. J. D. Mackenzie and D. R. Ulrich, p. 223). A problematic issue regarding xerogel synthesis is the high capillary pressures present at the final stages of solvent removal, when the liquid-air menisci recede in the small voids between the aggregating particles. These pressures can lead to substantial collapse of the porosity. For this reason, extraction of the solvent under controlled pressure/temperature conditions (a process termed supercritical extraction) is often employed, in which case the resulting porous solid is termed an aerogel. Historically, xerogels and aerogels have been the focus of the large majority of efforts to create porous sol-gel inorganic solids. For the reasons summarized above, the processes are slow, complex, and offer only a limited level of control over the resulting porous microstructure.
The incorporation of sacrificial porogens in the sol, particularly in organic (carbon-based) polymers that can be easily removed via thermolysis at elevated temperatures, is generally viewed as a more efficient method to obtain porous inorganic solids via the sol-gel synthetic route. To date, efforts have generally focused upon the fabrication of low dielectric constant (low-k) insulating films for the microelectronics industry. The most intensely studied sol-gel material for such applications is methyl silsesquioxane (MSSQ, chemical formula MeSiO3/2), obtained by using a special alkoxide precursor with some of the hydrolysable groups replaced by non-hydrolysable alkyl ligands [e.g. dimethyldiethoxysilane (CH3—)2Si(—OCH2CH3)2]. A large variety of organic porogens has been proposed as a means to template porosity in sol-gel silica, MSSQ and other sol-gel derived solids. These include, among others, star-shaped and hyper-branched poly(ε-caprolactone), poly(alkylene ether) homo- and copolymers (random, diblock and triblock including the Pluronic™ family), short-chain surfactants such as cetyltrimethylammonium bromide (CTAB), vinyl addition copolymers derived from vinyl pyridine, N,N-dimethyl acrylamide, aminoalkyl methacrylates, linear copolymers by copolymerization of methyl methacrylate and N,N-dimethylaminoethyl methacrylate, polyimides, poly(phenylquinoxalines) and poly(methylstyrene).
Importantly, porogen-based sol-gel synthesis can be achieved using a sacrificial template. The sacrificial template is an amphiphilic molecule capable of self-assembling in solution. This creates a highly-ordered liquid-crystalline (LC) nm-scale structure that guides the precursor molecules to co-assemble around the structure. Porous sol-gel inorganic solids obtained via such self-assembling templates are often referred to as mesoporous sieves and have been shown to exhibit remarkable structural properties. These include mesoscopic pore sizes, narrow pore size distributions, highly-ordered pore channel networks, mechanically robust pore walls, and extremely high surface areas (1000 m2/g or higher). Of particular importance is the case where the template assumes a cubic liquid-crystalline (LC) structure, because these lead to surface-accessible, highly-interconnected, continuous pore channel networks.
The unique properties of self-assembling template-assisted, sol-gel inorganic mesoporous materials has motivated much research effort over the last decade. In 1992, a group of researchers at Mobil Oil Corporation discovered the surfactant molecules would self-assemble in an aqueous solution of soluble silica, and upon solidification of the silica substrate, the surfactant could be removed leaving a mesoporous material (“MCM-41”) having a hexagonal honeycombed array of uniform mesopores (see U.S. Pat. Nos. 5,057,296 and 5,102,643, which are fully incorporated by reference). MCM-41 is synthesized using the cationic type surfactant, quaternary alkyltrimethylammonium salts and various silica sources, such as sodium silicates, tetraethyl orthosilicate, or silica gel, under hydrothermal conditions (Beck et. al., 1992, J. Am. Chem. Soc. 114, 10834). The pore size of MCM-41 can be adjusted from about 1.6 nm up to about 10 nm by using different surfactants or altering synthesis conditions.
A variety of other self-assembling template-assisted mesoporous inorganic oxide materials are described in a number of patents. U.S. Pat. No. 6,592,991 describes block copolymers as templates for structured organic-inorganic hybrid materials. U.S. Pat. Nos. 6,592,980 and 6,365,266 describe mesoporous films having reduced dielectric constants. U.S. Pat. No. 6,592,764 describes inorganic oxide materials. U.S. Pat. No. 6,541,539 describes porous oxides. U.S. Pat. No. 6,458,310 describes a process of making a polymeric material having a microporous matrix. U.S. Pat. No. 6,334,988 describes mesoporous silicates. U.S. Pat. No. 6,054,111 describes amphiphilic block copolymers as templates for the preparation of mesoporous solids. U.S. Pat. No. 5,622,684 describes porous inorganic oxide materials prepared by non-ionic surfactant templating.
Template-assisted mesoporous materials are fabricated using two broad classes of self-assembling amphiphilic templates: short molecules (often referred to as “surfactants”) and triblock copolymers. Surfactant-based methods are well described by Brinker et al. (Advanced materials 1999, 11 No. 7) and by Kresge et al. (Nature Vol 359 22 Oct 1992). The triblock copolymer template-based process (most relevant to the current invention) is described in US Patent No. 6,592,764 (fully incorporated by reference).
Mesoporous Materials used for Drug-Delivery
A number of scientific papers and patent documents refer to the use of mesoporous materials in medical or drug-related applications.
Vallet-Regi et al. (Chem. Mater. 2001, 13, 308-311) describe a powdered mesoporous material (MCM-41) that was charged with ibuprofen. Two mesoporous materials were used in this experiment each made using the surfactant templating method, and each with a different pore size (2.5 nm and 1.8 nm). But both appeared to absorb drug to the same degree and the weight percent ratio of drug to MCM-41 was 30% in both cases. The drug was shown to be released fairly steadily over a period of about 80 hours. In this case, the drug was loaded into MCM-41 by dissolving the drug in hexane and adding the MCM-41 compound to the hexane in a powdered form. Valelet-Regi et al. does not show or suggest that MCM-41 could be used to coat a surface and that a drug could then be loaded into the mesoporous coating.
Doadrio et al. (J. Controlled Release, 1997, 2004, 125-132) describe the use of HPLC techniques to measure the drug release characteristics of a mesoporous oxide (SBA-15) loaded with the antibiotic gentamicin. Gentamicin was loaded into SBA-15 by mixing SBA-15 powder to a saturated solution of drug over a period of three days. The material was then pressed into a disc, and both the disc and the drug-loaded powder were immersed into a simulated body fluid and drug release rates into the fluid were measured using HPLC.
Galarneau et al. (New J. Chem. 2003, 27:73-39) describes the microscopic and sub-microscopic structure of SBA-15. This paper details the structures of two distinct morphological forms of SBA-15—one having a synthesis temperature above 80° C. and one having a synthesis temperature below 80° C. When synthesized below 80° C. SBA-15 possesses mesopores with a diameter of about 5 nm and “ultramicropores” with a diameter <1 nm. When synthesized above 80° C. SBA-15 possesses mesopores with a diameter >9 mm and no “ultramicropores”.
Mal et al. (Nature Vol 421, 23 Jan 2003, 350-353) describe a method of controlling the absorption and release of a drug, coumarin, from the pore outlets of a mesoporous silica oxide, MCM-41, using photo-activated dimerization of coumarin derivatives. The mesoporous material was made using the surfactant templating method. In this experiment, the authors emphasize that successful absorption and release depends upon the MCM-41 material being filled with molecules of the template material that caused pore formation, and also upon the “one-dimensional, isolated nature of the individual pores . . . ” of the material. Mal et al. do not show a tri-block copolymer-derived mesoporous material with continuously interconnected channels that could be applied to a surface for use as a drug reservoir.
Munoz et al. (Chem. Mater. 2003, 15 500-503) describes an experiment which demonstrated that drug (ibuprofen) was delivered at a different rate from two different formulations of MCM-41, one made using a 16 carbon surfactant and one using a 12 carbon surfactant. As for the Valelet-Regi et al. paper, above, the drug was loaded into MCM-41 by dissolving the drug in hexane and adding the MCM-41 compound to the hexane in a powdered form. Munoz et al. do not show a tri-block copolymer-derived mesoporous material with continuously interconnected channels. The experiment does not show or suggest that MCM-41 could be used to coat a surface and that a drug could then be loaded into the mesoporous coating.
A number of other publications that may be relevant include the following.
WO0025841 describes a stent with a nonporous aluminum oxide coating. The coating has μm-deep, non-interconnected channels produced by electrochemical etching. The channels are oriented vertically with respect to the device surface. This stent has failed in clinical trials because the porous alumina chips or the stent surface.
WO0066190A1 discloses a porous silicon derivatized hydrosilylation that can be used in immunoisolation devices, biobattery devices, and optical devices.
U.S. Patent application publication No. 20020164380A1 describes the preparation of a mesoporous composition by adding a solvent to mixture of amphipathic compounds and alumina, then aging the mixture and purifying the product. It is suggested that these products may be useful in drug delivery vehicles.
WO9947570A1 describes the self assembly of microstructures useful in optical applications, tissue engineering and biomaterials and molecular electronic devices. p WO03055534A1 describes a fabric comprising silicon that is biocompatible and may also be able to act as an electrical conductor be used as a slow release means for drugs or fragrances, or as a collector for example for sweat.
WO9834723A2 (and EP0969922B1) describes a surface functionalized mesoporous material (SFMM) that has an ordered or organized array of functional molecules containing specific functional groups, with the functional molecules attached to the available surface area of the mesoporous substrate. The surface functionalized mesoporous material is useful for use in chemical separations.
WO0128529A1 describes a porous and/or polycrystalline silicon material used in the preparation of a pharmaceutical product for oral or rectal administration
WO9936357A1 describes a mesoporous material made by forming an aqueous solution having an organometallic compound; adding a solution comprising a pore forming material selected from the group consisting of monomeric polyols, polyacids, polyamines, carbohydrates, oligopeptides, oligonucleic acids, carbonyl functional organic compounds to form a sol gel matrix by polycondensation; drying the sol gel matrix; and removing the pore forming material from the dried sol-gel matrix to thereby form a mesoporous material. The mesoporous materials have pore diameters of from about 20 angstrom to about 100 angstrom and may be used with a biologically active agent immobilized within the pores of the mesoporous material.
U.S. Pat. No. 6,511,668 (and EP0872447A1) describes a non-flaky silicon oxide powder useful as the carrier for cosmetics, drugs and perfumes.
None of these references describe a drug-delivery device comprising a triblock copolymer template-based mesoporous surface coating with substantially continuously interconnected channels designed to function as a drug reservoir. Further, none describe such a drug reservoir coating that can be made easily and inexpensively, applied evenly and consistently, and wherein a drug may be loaded into the coating after deposition onto the surface of an implantable device.
Use of Mesoporous Materials to Enhance Adhesion
Another aspect of the invention is the use of mesoporous materials to enhance adhesion between organic polymer layers and inorganic surfaces.
Interfaces between such dissimilar materials pose certain challenges for adhesion. Most inorganic solids are usually covered with a hydrophilic native surface oxide that is characterized by the presence of surface hydroxyl groups (M-OH, where M represents an atom of the inorganic material, such as silicon or aluminum). At ambient conditions, at least a monolayer of adsorbed water molecules covers the surface, forming hydrogen bonds with these hydroxyl groups. Therefore, hydrophobic organic polymers do not spontaneously wet and adhere to the surface. Furthermore, even if polymer/surface bonds (including covalent bonds) are formed under dry conditions, these bonds are susceptible to hydrolysis upon exposure to water. This effect is particularly important in applications where devices or components containing organic/inorganic interfaces must operate in aqueous, corrosive environments such as the human body.
Two different approaches are traditionally followed to reinforce organic/inorganic interfaces. The first is chemical modification of the inorganic surface via amphiphilic silane coupling agents that improve polymer wetting, bonding and interface resistance to water. The second is the introduction of controlled roughness or porosity on the inorganic surface that induces polymer mechanical interlocking.
Silane coupling agents are materials that exhibit both hydrophilic and hydrophobic behavior, and are thus termed amphiphilic. Their molecules have the general structure Y(CH2)nSiX3, comprising a carbon chain (typically n<20), three hydrolysable groups (X) that form hydrophilic silanols (Si—OH) in solution, and a hydrophobic group (Y) selected for chemical affinity with the polymer of interest.
When a hydrophilic inorganic surface is treated with a silane solution, the hydrophilic silanols undergo condensation reactions with surface hydroxyl groups forming oxane bonds with the surface (Si—O—M). Similar to polymer/substrate bonds, silane/substrate oxane bonds are susceptible to hydrolysis but at rates several orders of magnitude lower. Siloxane bonds (Si—O—Si) also form by condensation of silanols belonging to adjacent coupling agent molecules. Additionally, the hydrophobic silane groups improve the polymer wetting of the treated surface by lowering the surface energy. Partially cross-linked coupling agent oligomers can diffuse in the polymer matrix and improve the adhesion by mechanical interlocking. If the reactivity of the hydrophobic end group is tailored to match that of the polymer, the interface can be further strengthened by co-polymerization and covalent silane/polymer bonding.
While silane groups have been used to improve adhesion between organic/inorganic interfaces and reduce hydrolysis, there remains a need for further improvements especially in aqueous, corrosive environments.
Attempts to engineer the interface morphology to improve adhesion typically focus on introducing roughness or porosity to the inorganic surface. The rough or porous surface can be created either by selective material removal from an initially flat surface or by deposition of a porous film.
Polymer wetting of the rough or porous surface results in increased contact area, so that more bonds can be established between the two materials. Furthermore, the adhesion can be improved by a change in the failure mode. A perfectly flat organic/inorganic interface will generally fail adhesively, by crack propagation along the weakest-link path in the microstructure. In contrast, rough morphology results in mechanical interlocking of the polymer and pore impregnation creates a composite phase in the interface region. Crack propagation will now likely occur by both interface adhesive and polymer cohesive failure. The latter is associated with crazing, a process in which polymer fibrils bridge the de-bond opening and connect the two mating fracture surfaces behind the crack tip. The fibrils undergo plastic deformation before rupture, dissipating energy and increasing the macroscopic interface fracture resistance.
Some attempts have been made to use nanporous silica to improve adhesion, and Annapragada (U.S. Pat. No. 6,465,365) teaches the use of nanporous silica films to improve the adhesion of an inorganic film and an inorganic substrate. Rutherford et al. (U.S. Pat. No. 6,318,124) teaches the use of nanporous silica on an inorganic substrate with an organic polymer coating.
In light of this background, there remains a need in the art for materials that allow improved adhesion between organic and inorganic interfaces especially in aqueous environments.
Additionally there is a need for a non-polymeric drug reservoir material that may be applied to the surface of an implantable medical device.